Vitamin 1

Disorders

bone mineral density at the femoral neck and lumbar spine have been documented
(Kneissel et al. 2005, Rohde and DeLuca 2003, Promislow et al. 2002, Melhus et
al. 1998). Dietary intake of 1500 g or more per day is associated with osteoporosis
and an increased risk of hip fractures (Melhus et al. 1998, Michaelsson et al. 2003,
Feskanich et al. 2002, Lips 2003), in some instances as much as doubling the risk.
These findings were only noted with excess intake of preformed vitamin A (retinol)
and not beta-carotene.
There is no known deficiency state for carotenoids and no RDAs. Beta-carotein
is also widely considered to be nontoxic, and humans tolerated high doses without
apparent harm. There is no evidence that conversion of beta-carotene to vitamin A
contributes to toxicity of the latter, even when beta-carotene is ingested in large
amounts. The only undesirable effect of high beta-carotene intake is a yellowish
discoloration of the skin, or carotehnemia, which occurs only at extremely high
intake (Mathews-Roth 1986).

10.4.2 VITAMIN D
Vitamin D is not a true vitamin. It can be synthesized in the human body, and
therefore functions more as a pro-hormone. Vitamin D is a general term referring
to the final biologically active product as well as its numerous precursors. It is a
lipid-soluble compound related in structure to the cholesterol molecule. The two
forms of vitamin D are ergocalciferol (D2) and cholecalciferol (D3). Vitamin D2 is
formed by the ultraviolet irradiation of ergosterol and is found in plants, while
vitamin D3 is primarily found in animal products. It was previously believed that
both forms have similar metabolism and biological function, but Armas et al.
(2004) recently showed that vitamin D3 is over three times more potent than D2.
Dietary sources of vitamin D3 include egg yolks, fish liver oils, and fortified
foods. The major source, however, is synthesized in the skin by converting 7-
dehydrocholesterol to vitamin D3 with adequate sunlight exposure. Vitamin D
from either source is bound to vitamin D-binding protein and transported to the
liver, where it is hydrox- ylated by 25-vitamin D-hydroxylase to 25-hydroxy-
vitamin D, or calcidiol. In the kidneys, 25(OH)D is further hydroxylated by 1-
alpha-hydroxylase to 1,25-dihy- droxy-vitamin D (1,25(OH)2D), or calcitriol. A
smaller amount of relatively inactive 24,25(OH)2D is also synthesized in the liver.
Calcitriol is the most active form of vitamin D. The affinity of the nuclear
receptor for 1,25(OH)2D is approximately 1000 times that for 25(OH)D. Serum
levels of calcitriol, however, do not necessarily reflect total body stores of the
vitamin due to the relatively short half-life of 4 to 6 hours. Calcidiol, on the other
hand, has a half-life of approximately 3 weeks (Thomas and Demay 2000) and is a
better measure of vitamin D status (Johnson et al. 2002). Vitamin D deficiency is
common in the elderly and can have serious conse- quences. Despite the ability
to store vitamin D, studies have shown that both 1,25(OH)2D and 25(OH)D serum
levels decline with age. Up to 25% of community- dwelling elderly may have
vitamin D deficiency, and the prevalence can be as high as 80% in residents of
long-term-care facilities. Several changes associated with aging result in age
being a risk factor for vitamin D deficiency. Decreased exposure to sunlight and
decreased amounts of 7-dehydrocholesterol levels in the aging skin
deprive the elderly of the major source of vitamin D that younger adults enjoy. In
the absence of adequate photoconversion, dietary intake becomes a much more
crucial source of vitamin D. This, however, occurs at a time when dairy products
and other vitamin D-rich foods constitute a declining part of the typical geriatric
diet. Decreased renal conversion of 25(OH)D to 1,25(OH)2D and, to a lesser
degree, decreased hepatic hydroxylation of D to 25(OH)D further limit availability
of the active form of vitamin D. Finally, several medications disrupt vitamin D
absorption, activation, or function. Most notable are anticonvulsants, rifampin,
ketoconazole, primidone, and many other drugs that can impair hydroxylation or
accelerate elim- ination by activating the cytochrome P-450 system. The new DRIs
account for these age-related changes. The Adequate Intake (AI) is set at 400 IU
(10 g) for individuals age 51 to 70 years and 600 IU (15 g) for those over the age
of 70. High-risk elderly may benefit from 800 IU/day, which has been shown to
increase bone mineral density and decrease the risk of bone fracture. These levels
of intake can easily be achieved with a multivitamin (most containing 200 IU)
twice a day or a plain vitamin D supplement. Concurrent calcium supplementation
is advised since the typical adult diet does not meet calcium requirements (Kamel
and Hajjar 2003). Most vitamin D preparations are supplemented with 250 to 600
mg calcium.
Biochemical manifestations of vitamin D deficiency include hypocalcemia,
hypophosphatemia, and elevated alkaline phosphatase. With prolonged hypocalce-
mia, secondary hyperparathyroidism may develop, which further decreases phos-
phorus levels and promotes bone resorption by stimulating osteoclasts. Clinical
features of these changes include accelerated osteoporosis and an increased risk of
vertebral and long bone fracture. Vitamin D deficiency may also present with any
of the symptoms of hypocalcemia, such as neuromuscular irritability, neuropathy,
hyperesthesia, and proximal myopathy or pain.
The benefits of supplementing vitamin D in the elderly have been documented
in many studies. In a study of 3270 elderly women (mean age, 84 years; SD, 6
years), Chapuy et al. (1992) demonstrated a 43% decrease in hip fractures (p =
0.043) and a 32% decrease in total nonvertebral fractures (p = 0.015) in the
treatment group compared to the placebo group. Treatment consisted of 800 IU
vitamin D with 1200 mg calcium daily for 18 months. In a subgroup analysis (n =
56), bone mineral density (BMD) at the proximal femur increase by 2.7% in the
treatment group, compared to a decrease of 4.6% in the placebo group (p < 0.001).
The preventive effect of calcium and cholecalciferol supplementation on fracture
risk continued after an additional 18 months of follow-up (Chapuy et al. 2002). At 3
years total follow-up, hip fractures and all nonvertebral fractures were reduced in
the treatment group by 29 and 24%, respectively (p < 0.01 in both cases). The
intention to treat analysis showed 17.2% fewer subjects with at least one vertebral
fracture (p < 0.02) and 23.0% fewer subjects with hip fractures (p < 0.02).
Similar results have been reported by other investigators, though not
consistently. Dawson-Hughes et al. (1991) showed that in wintertime, when
vitamin D levels dip, spinal bone loss was significantly less in postmenopausal
women consuming at least 500 IU vitamin D plus calcium compared to the control
group. During the summer months, supplementation was associated with a net gain
in BMD. The same group of investigators later showed that daily supplementation
with a low dose of vitamin
D (100 IU) plus calcium was sufficient to limit spinal bone loss at 2 years follow-
up, but higher doses (700 IU) were necessary to minimize bone loss from the
femoral neck (Dawson-Hughes et al. 1995). Since then, the RDA for vitamin D was
increased, as discussed earlier. These trials, however, should not lull the public into
a false sense of complacency, as the benefit of vitamin D and calcium on BMD
does not continue unabashed. The natural history of osteoporosis is one of a gradual
contin- uous bone loss, starting in early adulthood, and preventive interventions
only retard the rate of bone loss, not prevent it. In a follow-up study, the effect of
700 IU vitamin D and 500 mg calcium on BMD of the femoral neck and spine was
statistically significant compared to placebo after 1 year, but not in the second or
third year of follow-up (Dawson-Hughes et al. 1997).
Since most interventional studies combined various amounts of vitamin D and
calcium supplements, it is not clear how much benefit is derived from each compo-
nent. It has been suggested that a significant component of the benefit is due to
calcium supplementation in calcium-deficient elderly. In a 4-year study of 438
elderly subjects with a baseline median calcium intake of 546 mg/day and median
serum 25(OH)D of 59 nmol/l (normal > 75 to 80 nmol/l), Peacock et al. (2000)
supplemented subjects daily with 750 mg calcium or 15 g (600 IU) 25(OH)D. At
4 years follow- up, calcium reduced bone loss, secondary hyperparathyroidism, and
bone turnover, whereas 25(OH)D was intermediate between placebo and calcium.
Fracture rates were similar among the groups. The authors concluded that the
beneficial effect of vitamin D is due to the reversal of calcium insufficiency.
Findings are in line with those of Lips et al. (1996), who showed no decrease in the
incidence of hip fractures and other peripheral fractures with vitamin D
supplementation (400 IU/day) after a median follow-up of 3.5 years. The mean
baseline dietary intake of calcium from dairy products was 868 mg/day, and the
mean serum 25(OH)D concentration in the third year of the study was 60 nmol/l in
the vitamin D group. It is quite possible, though, that these results reflect dose-
related outcomes. In a recent meta-analysis of randomized controlled trials (RCTs)
a vitamin D dose of 700 to 800 IU/day reduced the relative risk (RR) of hip
fractures by 26% (RR, 0.74; 95% confidence interval (CI), 0.61 to 0.88) and
nonvertebral fractures by 23% (RR, 0.77; 95% CI, 0.68 to 0.87) vs. calcium and
placebo (Bischoff-Ferrari et al. 2005). No significant benefit was observed in the
RTCs with 400 IU/day vitamin D supplement. Based on currently available
evidence, most experts advise supplementing high-risk individuals, which includes
most of the geriatric population, with no less than 400 to 600 IU vitamin D and 800
to 1000 mg calcium daily, with the remaining balance obtained by diet. While daily
oral supplementation is the preferred means of administering vitamin D, high-dose
biannual oral replacement (10,000 to 100,000 IU) or annual intramuscular
injections (150,000 IU) have been used and appear to be well tolerated
(Heikenheimo et al. 1991, Holick 1994).
Other effects of vitamin D replacement have been studied. Vitamin D nuclear
receptors are found in most human cells and tissues, including skeletal muscles. It
is not unexpected, therefore, to anticipate various systemic effects of vitamin D, due
to either direct receptor activation or indirect effect of calcium metabolism. Vitamin
D serum levels have been found to correlate with muscle strength (Bischoff et al.
1999), and supplementation improved functional outcome as measured by the Frail
Elderly Functional Assessment (FEFA) questionnaire (Gloth et al. 1995). In frail
elderly women with a mean age of 85.3 years, daily vitamin D (800 IU) plus
calcium (1200 mg) over a 3-month period reduced the risk of falls by 49%
compared to calcium alone (Bischoff et al. 2003). The investigators hypothesized
that the impact of vitamin D on falls could be related to the observed improvement
in musculoskel- etal function. The reduced fall risk in women appears to continue
beyond the short term. A 3-year trial of cholecalciferol (700 IU) and calcium (500
mg) dietary supplementation reduced the odds of falling in ambulatory older
women by 46% (odds ratio (OR), 0.54; CI, 0.30 to 0.97), but not in men (OR, 0.93;
CI, 0.50 to 1.72) (Bischoff-Ferrari et al. 2006). In less active women, fall reduction
was even greater. The gender discrepancy is not fully explained, though mean
baseline 25(OH)D in men was significantly higher than in women, falling in the
low-normal range. In a meta-analysis of RCTs, vitamin D supplementation
appeared to reduce the risk of falls among all older individuals by more than 20%
(Bischoff-Ferrari et al. 2004). From the pooled risk difference, the number needed
to treat was 15 (95% CI, 8 to
53) to prevent one fall. While these early studies show promising results, they are
limited by the relatively small number of participants and short follow-up period.
Clearly more clinical trials are needed prior to establishing evidence-based clinical
recommendations with any degree of confidence.
Vitamin D toxicity is rare but does occur. Most commonly, toxicity is due to
prolonged ingestion of high doses of vitamin D, usually 50 to 100 times the daily
requirement in the elderly (Johnson et al. 2002). Chronic renal insufficiency, par-
athyroid disease, hypercalcemia, and granulomatous diseases increase the risk of
toxicity. Symptoms generally are those of hypercalcemia. Serum and urine calcium
levels should be monitored as an indicator of vitamin D toxicity. Excessive sunlight
exposure will not lead to vitamin D toxicity with normal oral intake.

10.4.3 VITAMIN E
Vitamin E exists in nature as eight related fat-soluble compounds, the tocopherols
and tocotrienols, each in alpha, beta, gamma, and delta form. All are potent antiox-
idants. Alpha-tocopherol is the most biologically active of the tocopherols, though
gamma-tocopherol is more prevalent in the human diet. Human trials have almost
exclusively been conducted with alpha-tocopherol due to its potency. Dosing and
RDA for vitamin E are reported either in milligrams as alpha-tocopherol equivalents
(ATE), to account for different activities of the various forms of vitamin E, or in
international units (IU). For conversion, 1 mg ATE equals 1.5 IU. Vitamin E is
marketed with a d or dl designation, indicating the natural or synthetic form,
respec- tively. The natural form, also known as RRR-alpha-tocopherol, is more
active and better absorbed. Sources of vitamin E include egg yolk, leafy vegetables,
wheat germ, various nuts, vegetable oils, margarine, and legumes. As with other
fat-soluble compounds, intestinal absorption of vitamin E requires micelle and
chylomicron formation and adequate production of bile acid. In the bloodstream,
vitamin E is dispersed by a variety of lipoprotein transportation pathways after
chylomicrons are broken down by lipoprotein lipase. Chylomicron remnant
reuptake occurs in the liver in a process that is not fully explained, and vitamin E is
excreted back into the